rs7671781

Positions:

chr4-168512176-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001166108.2(PALLD):c.672G>A(p.Met224Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,613,202 control chromosomes in the GnomAD database, including 78,961 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M224T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.29 ( 6561 hom., cov: 32)

Exomes 𝑓: 0.31 ( 72400 hom. )

Consequence

PALLD
NM_001166108.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -4.94

Variant links:

Genes affected

PALLD (HGNC:17068): (palladin, cytoskeletal associated protein) This gene encodes a cytoskeletal protein that is required for organizing the actin cytoskeleton. The protein is a component of actin-containing microfilaments, and it is involved in the control of cell shape, adhesion, and contraction. Polymorphisms in this gene are associated with a susceptibility to pancreatic cancer type 1, and also with a risk for myocardial infarction. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

PALLD links:

DDX60L (HGNC:26429): (DExD/H-box 60 like) This gene encodes a member of the DExD/H-box helicase family of proteins, a subset of the super family 2 helicases. Members of the DExD/H-box helicase family share a conserved functional core comprised of two RecA-like globular domains. These domains contain conserved motifs that mediate ATP binding, ATP hydrolysis, nucleic acid binding, and RNA unwinding. In addition to functions in RNA metabolism, members of this family are involved in anti-viral immunity and act as cytosolic sensors of viral nucleic acids. The protein encoded by this gene has been shown to inhibit hepatitis C virus replication in response to interferon stimulation in cell culture. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

DDX60L links:

LOC107986198 (HGNC:):

LOC107986198 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010214746).

BP6

Variant 4-168512176-G-A is Benign according to our data. Variant chr4-168512176-G-A is described in ClinVar as [Benign]. Clinvar id is 403285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PALLD	NM_001166108.2 link	c.672G>A	p.Met224Ile	missense_variant	2/22	ENST00000505667.6	NP_001159580.1	Q8WX93-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PALLD	ENST00000505667.6 link	c.672G>A	p.Met224Ile	missense_variant	2/22	1	NM_001166108.2	ENSP00000425556.1		Q8WX93-9

Frequencies

GnomAD3 genomes

AF:

0.293

AC:

44444

AN:

151670

Hom.:

6556

Cov.:

show subpopulations

Gnomad AFR

AF:

0.246

Gnomad AMI

AF:

0.388

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.281

Gnomad EAS

AF:

0.191

Gnomad SAS

AF:

0.219

Gnomad FIN

AF:

0.394

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.330

Gnomad OTH

AF:

0.280

GnomAD3 exomes

AF:

0.281

AC:

70311

AN:

250460

Hom.:

10540

AF XY:

0.282

AC XY:

38208

AN XY:

135350

show subpopulations

Gnomad AFR exome

AF:

0.246

Gnomad AMR exome

AF:

0.180

Gnomad ASJ exome

AF:

0.297

Gnomad EAS exome

AF:

0.176

Gnomad SAS exome

AF:

0.222

Gnomad FIN exome

AF:

0.399

Gnomad NFE exome

AF:

0.325

Gnomad OTH exome

AF:

0.294

GnomAD4 exome

AF:

0.311

AC:

454076

AN:

1461412

Hom.:

72400

Cov.:

AF XY:

0.309

AC XY:

224372

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.244

Gnomad4 AMR exome

AF:

0.188

Gnomad4 ASJ exome

AF:

0.298

Gnomad4 EAS exome

AF:

0.194

Gnomad4 SAS exome

AF:

0.225

Gnomad4 FIN exome

AF:

0.393

Gnomad4 NFE exome

AF:

0.326

Gnomad4 OTH exome

AF:

0.297

GnomAD4 genome

AF:

0.293

AC:

44463

AN:

151790

Hom.:

6561

Cov.:

AF XY:

0.292

AC XY:

21619

AN XY:

74134

show subpopulations

Gnomad4 AFR

AF:

0.246

Gnomad4 AMR

AF:

0.241

Gnomad4 ASJ

AF:

0.281

Gnomad4 EAS

AF:

0.191

Gnomad4 SAS

AF:

0.219

Gnomad4 FIN

AF:

0.394

Gnomad4 NFE

AF:

0.330

Gnomad4 OTH

AF:

0.276

Alfa

AF:

0.307

Hom.:

5209

Bravo

AF:

0.280

TwinsUK

AF:

0.309

AC:

1147

ALSPAC

AF:

0.333

AC:

1284

ESP6500AA

AF:

0.242

AC:

1065

ESP6500EA

AF:

0.305

AC:

2624

ExAC

AF:

0.285

AC:

34602

Asia WGS

AF:

0.196

AC:

683

AN:

3478

EpiCase

AF:

0.319

EpiControl

AF:

0.315

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 2020	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Pancreatic cancer, susceptibility to, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.0020

DANN

Benign

0.80

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.19

T;T;T

MetaRNN

Benign

0.0010

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.090

N;N;N

REVEL

Benign

0.045

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.49

T;T;T

Vest4

0.030

MutPred

0.19

Gain of glycosylation at S220 (P = 0.0087);Gain of glycosylation at S220 (P = 0.0087);.;

MPC

0.22

ClinPred

0.014

GERP RS

-11

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over